Genetic Linkage connects new research findings, based on the wiring of my brain after years of writing a human genetics textbook and lots of articles. Here, the linking of sense and nonsense.

The excitement of genetic research these days is when genome sweeps of people sharing a disease reveal possible responsible genes. That’s what happened when researchers at the Perelman School of Medicine at the University of Pennsylvania looked at genomic landmarks among 1,114 brains from people who had died of progressive supranuclear palsy (PSP), a form of dementia that affects movement.

PSP is a “tauopathy,” in which the dark gummy protein tau, of Alzheimer’s fame, smothers the brain. Compared to unaffected brains, the PSP brains differ in three genome neighborhoods, harboring three new
candidate genes that make sense: one impairs brain cells’ abilities to untangle misfolded proteins, another boots misfolded proteins out of cells, and a third may help wrap brain cells in insulating myelin. New drug targets!

In genetics nonsense is important too. A nonsense mutation inserts a “stop” right smack in the middle of a gene, like a period in the middle of a sentence. It shortens the encoded protein, causing some 1800 diseases. Ignoring a nonsense mutation can restore function, like saving a sentence truncated by an errant period with a stroke of white-out. The idea isn’t new – researchers discovered that bacteria can read-through nonsense mutations in the 1960s, and that certain common antibiotics, such as gentamicin, enable cells to read-through nonsense. Those drugs may provide old-fashioned (cheap) treatments for genetic diseases such as Rett syndrome. Alas, early attempts at treating cystic fibrosis, hemophilia, and Duchenne muscular dystrophy by suppressing nonsense mutations didn’t work because the antibiotic doses necessary would be toxic.

Now Yi-Tao Yu and co-workers at the University of Rochester report in Nature that they have invented a way to mimic antibiotic-mediated nonsense suppression. They’ve used a synthetic RNA to chemically tweak nonsense codons so that they are instead read as bona fide amino acids, in essence altering the genetic code. So far this approach, dubbed RNA modification, works in a test tube. But carefully-directed nonsense suppression holds enormous promise for correcting many genetic diseases. Stay tuned!